U.S. Pat. No. 4,604,463 describes the preparation of 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (I) by condensation of 7-ethyl-10-hydroxycamptothecin (II) with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (III) in pyridine at room temperature.
According to WO200519223 this method leads to coloured impurities in the product. In order to avoid these, 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin was prepared by condensation of
7-ethyl-10-hydroxycamptothecin of formula
with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride of formula
in a polar aprotic solvent such as acetonitrile and in the presence of 4-dimethyl-aminopyridine. The condensation proceeds in suspension, where the polar aprotic solvent dissolves only 4-dimethylaminopyridine whereas 7-ethyl-10-hydroxycamptothecin and 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride in this polar aprotic solvent remain undissolved. The amount of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride employed in the condensation reaction is preferably 1.3 to 3 mol, more preferably 1.6 to 1.9 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin. The amount of 4-dimethylaminopyridine used in the condensation ranges preferably between 1.5 and 4 mol, more preferably between 1.8 and 2.2 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin. The amount of the polar aprotic solvent used in the condensation is preferably 400 to 600 mol, more preferably 430 to 460 mol, per mol of 7-ethyl-10-hydroxycamptothecin. The condensation is performed preferably at a temperature from 70 to 80° C., more preferably at 73 to 77° C.